Inflammatory cytokines are biological factors that play important roles in suppressing pathogenic infectious diseases and the like, but inflammatory cytokines can cause inflammatory diseases such as toxic shock syndrome, osteoarthropathy, diabetes or inflammatory bowel disease when they are produced excessively.
Concerning these inflammatory diseases, biologics focusing on the functional antagonism of tumor necrosis factor α (hereinafter referred to as “TNFα”), which is one of inflammatory cytokines, have been actively studied. For example, infliximab, which is a monoclonal antibody against TNFα, has been developed as a therapeutic agent for inflammatory diseases such as uveitis by Behcet's disease or Crohn's disease, since it acts potently in the body as a functional antagonist of TNFα (Koj, Biochim. Biophys. Acta, 1996, Vol. 1317, pp. 84-94 and Dinarello, Rev. Infect. Disease, 1984, Vol. 6, pp. 51-95).
On the other hand, it is known that p38 MAPK, which is a homolog of Mitogen-Activated Protein Kinase (hereinafter referred to as “MAPK”), is activated by stimulation by ultraviolet radiation, lipopolysaccharide (hereinafter referred to as “LPS”), inflammatory cytokines or the like, thereby promoting production of inflammatory cytokines such as TNFα.
WO 99/00357, Japanese Unexamined Patent Application Publication No. 2001-526276, WO 02/083642, WO 07/103,468, Japanese Unexamined Patent Application Publication Nos. 2007-145819, 2006-528986, 2005-508357, 2003-512378 and 2002-517486, WO 00/043384 and WO 93/014081 disclose low molecular weight compounds having a p38 MAPK inhibitory activity, and WO 07/073,503, WO 04/082687 and Japanese Unexamined Patent Application Publication (JP-A) No. 1991-261755 disclose compounds having a 2,3-dihydro-1H-indene-2-yl urea structure. However, there is no disclosure or suggestion as to relationship between a 2,3-dihydro-1H-indene-2-yl urea structure and a p38 MAPK inhibitory activity, and there is no report as to 2,3-dihydro-1H-indene-2-yl urea derivatives having a p38 MAPK inhibitory activity.
Allergic dermatitis is a disease caused due to an allergic reaction and characterized by chronic itching and/or rash on the face, neck, elbow and/or knee. Due to increase of allergens and/or change in dietary habits, etc., the number of patients suffering from allergic dermatitis is increasing year by year and their symptoms tend to be more serious. Treatment of allergic dermatitis is performed mainly by pharmacotherapy and, as therapeutic agents in that case, adrenocortical steroids, immunosuppressive agents, antihistaminic agents and so on are used.
Inflammatory bowel disease is a generic term of diseases mainly causing inflammation and/or ulcer on mucosa of the colon, as typified by ulcerative colitis and Crohn's disease, and this disease is an intractable chronic disease of unknown etiology. A large number of patients are juvenile onset. Diarrhea, blood stool and so on continue for a long period of time, and relapse and remission are repeated. Hence, influence on QOL (Quality of life) of patients is large. Nevertheless, the number of patients is rapidly increasing in recent years. Treatment of inflammatory bowel disease is performed mainly by elemental diet therapy and/or pharmacotherapy. As therapeutic agents in case of pharmacotherapy, 5-aminosalicylic acid preparations, steroids, immunosuppressive agents, antibody preparations and so on are used.
Pain is classified into two types: acute pain which is physiological pain and chronic pain as typified by inflammatory pain and neuropathic pain. In chronic pain, pain lasts for a long time even after disappearance of the substantial tissue damage that caused the initial pain, and the causes thereof are thought to be abnormalities in pain transmission, control or recognition mechanism. Chronic pain is often resistant to opioid analgesics and so on, and is intractable. In addition, pain lasts for a long time, and dysesthesia such as hyperalgesia and/or allodynia occurs. Hence, QOL of patients is markedly reduced. Treatment of chronic pain is performed mainly by pharmacotherapy. As therapeutic agents in that case, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are used for inflammatory pain; and anticonvulsants, antidepressants and so on are used for neuropathic pain.
However, in treatment of inflammatory diseases caused by increase in TNFα, biologics such as infliximab may be expected to have a marked therapeutic effect as a functional antagonist, but are necessary to be administered as an injection solution, and therefore the burden on patients is heavy. In addition, such biologics have a risk that their efficacy may be greatly reduced in cases where they are recognized as foreign substances in the body when administered. Accordingly, development of a low molecular weight compound suppressing the TNFα production is desired, but a low molecular weight compound that has no possibility of side effects such as hepatotoxicity has not yet been discovered.
In treatment of allergic dermatitis, dermatitis symptoms are alleviated by using adrenocortical steroids, immunosuppressive agents and/or antihistaminic agents. However, at present, the effect is transient and the use of them is associated with a risk of infectious diseases and/or serious side effects.
In treatment of inflammatory bowel disease, elemental diet therapy has few side effects but greatly affects QOL of patients when the therapy is continued for a long period of time. On the other hand, in case of pharmacotherapy, there are poor response cases and many problems such as infectious diseases and complications.
In treatment of inflammatory pain, nonsteroidal anti-inflammatory agents, as typified by diclofenac sodium, are useful, but they have side effects such as gastrointestinal disorders. On the other hand, in treatment of neuropathic pain, gabapentin, which is an anticonvulsant, is useful, but it also has side effects such as pretty strong drowsiness and staggering.
Thus, it could be helpful to provide a low molecular weight compound which has a p38 MAPK inhibitory activity and a TNFα production suppressing activity associated therewith, and in which a good in vivo pharmacokinetic profile as a pharmaceutical and decrease in hepatotoxicity have been achieved, and a medical use thereof. It could also be helpful to provide a therapeutic or prophylactic agent for allergic dermatitis, inflammatory bowel disease or pain, comprising this low molecular weight compound as an effective ingredient.